Process for the preparation of N-[(1-n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide and salts and intermediates in the process

ABSTRACT

A process for the preparation of SB 207266 or a pharmaceutically acceptable salt thereof, which process comprises the reaction of N-(1- n  butyl-4-piperidyl)methylamine with a compound of formula (A), ##STR1## wherein R is alkyl.

This invention relates to a new synthetic process to a compound havingpharmacological activity.

WO93/18036 (SmithKline Beecham plc) describes compounds having 5-HT₄receptor antagonist activity of formula (I), or a pharmaceuticallyacceptable salt thereof: ##STR2## wherein X is O, S, SO, SO₂, CH₂, CH orNR wherein R is hydrogen or C₁₋₆ alkyl;

A is a saturated or unsaturated polymethylene chain of 2-4 carbon atoms;

R₁ and R₂ are hydrogen or C₁₋₆ alkyl;

R₃ is hydrogen, halo, C₁₋₆ alkyl, amino, nitro or C₁₋₆ alkyl;

R₄ is hydrogen, halo, C₁₋₆ alkyl or C₁₋₆ alkoxy;

Y is O or NH;

Z is of sub-formula (a), (b) or (c): ##STR3## wherein

n¹ is 1, 2, 3or 4; n² is 0, 1, 2, 3or 4; n³ is 2, 3, 4or5;

q is 0, 1, 2or 3; p is 0, 1 or 2; m is 0,1, or 2;

R₅ is hydrogen, C₁₋₁₂ alkyl, aralkyl or R₅ is (CH₂)_(z) -R₁₀ wherein zis 2 or 3 and R₁₀ is selected from cyano, hydroxyl, C₁₋₆ alkoxy,phenoxy, C(O)C₁₋₆ alkoxy, COC₆ H₅, -CONR₁₁ R₁₂, NR₁₁ COR₁₂, SO₂ NR₁₁ R₁₂or NR₁₁ SO₂ R₁₂ wherein R₁₁ and R₁₂ are hydrogen or C₁₋₆ alkyl; and

R₆, R₇ and R₈ are independently hydrogen or C₁₋₆ alkyl; and

R₉ is hydrogen or C₁₋₁₀ alkyl;

or a compound of formula (I) wherein the CO-Y linkage is replaced by aheterocyclic bioisostere;

having 5-HT₄ receptor antagonist activity.

Examples of alkyl or alkyl containing groups described herein includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ or C₁₂ branched, straightor cyclic alkyl, as appropriate. C₁₋₄ alkyl groups include methyl,ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

The pharmaceutically acceptable salts of the compounds of the formula(I) include acid addition salts with conventional acids such ashydrochloric, hydrobromic, boric, phosphoric, sulfuric acids andpharmaceutically acceptable organic acids such as acetic, tartaric,maleic, citric, succinic, benzoic, ascorbic, methanesulfonic, α-ketoglutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternaryderivatives of the compounds of formula (I) such as the compoundsquaternised by compounds R_(x) -T wherein R_(x) is C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and T is a radical correspondingto an anion of an acid. Suitable examples of R_(x) include methyl, ethyland n- and iso-propyl; and benzyl and phenethyl. Suitable examples of Tinclude halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internalsalts such as N-oxides.

The compounds of the formula (I), their pharmaceutically acceptablesalts, (including quaternary derivatives and N-oxides) may also formpharmaceutically acceptable solvates, such as hydrates, which areincluded wherever a compound of formula (I) or a salt thereof isreferred to.

Example 3 describes the hydrochoride salt of the compound of formula(I):

A is --CH₂ --(CH2)_(r) --CH₂ -- wherein r is 1;

R₁ and R₂ are hydrogen;

R₃ is hydrogen;

R₄ is hydrogen;

Y is NH; and

Z is of sub-formula (a), and is of structure (i): ##STR4##

This compound is N-[(1-^(n)butyl4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideSB 207266, (the hydrochloride salt is SB 207266-A) which is beingdeveloped by SmithKline Beecham plc as the active ingredient in amedicament for treatment of irritable bowel syndrome.

Example 3 of WO93/18036 describes a method of preparation of SB 207266-Afrom N-[(1-^(n) butyl4-piperidyl)methyl]indole-3-carboxamide (i.e. thecompound corresponding to SB 207266, without the oxazino moiety), byreacting with N-chlorosuccinimide and 3-bromo-1-propanol, followed bytreatment with sodium carbonate. N-[(1-^(n)butyl-4-piperidyl)methyl]indole-3-carboxamide is prepared by couplingN-(1-^(n) butyl-4-piperidyl)methylamine with a indole-3-carboxylic acid.

An alternative process for preparing SB 207266-A has now been discoveredwhich involves the use of the N-(1-^(n) butyl4-piperidyl)methylamineintermediate at a later stage in the process thus resulting in anincreased yield of SB 207266-A relative to the amount of thisintermediate, which is relatively expensive to produce.

Accordingly, the present invention provides a process for thepreparation of SB 207266 or a pharmaceutically acceptable salt thereof,which process comprises the reaction of of N-(1-^(n)butyl-4-piperidyl)methylamine with a compound of formula (A): ##STR5##wherein R is alkyl, such as methyl or ethyl.

The compound of formula (A) wherein R is methyl is methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.

The conditions and reagents for this reaction are similar to thosedescribed in the literature. A mixture of the amine and ester in asuitable solvent (eg toluene) is treated with a solution oftrimethylaluminum in toluene or hexanes at ambient temperature. Theresulting solution is then heated, preferably to reflux (112° C.) forabout four hours until the reaction is complete. The reaction is cooledto about 70° C. and quenched by cautious addition of aqueous sodiumhydroxide solution. The aqueous layer is separated and the mixturewashed once more with caustic and twice with water maintaining thetemperature at about 70° C. The product is isolated as described in theattached Example.

Alternative catalysts include NaH₂ Et₂ Al which is used in a similar wayto AlMe₃.

BuLi is also suitable but is used at lower temperatures and requires twoequivalents of the base and two equivalents of the amine.

The mechanism of the reaction and role of the aluminum or lithium basedcatalyst is discussed in the references listed below:

Use of AlMe₃ : Anwer Basha, Michael Lipton and Steven M. Weinreb,Tetrahedron Letters, 48, 4171, 1977.

Use of NaH₂ Et₂ Al: Tae Bo Sim and Nung Min Yoon, Synlett., 1994, 827

Use of BuLi: Kim-Wen n Yang, Joseph, G. Cannon and John G. Rose,

Tetrahedron Letters, 21, 1791, 1970

The oxazinoindole compound of the formula (A) is prepared from thecorresponding indole by reaction with N-chlorosuccinimide and a3-halo-propanol, such as 3-chloropropane or 3-bromopropanol followed bycyclisation of the intermediate (B) by treatment with base in a suitablesolvent. ##STR6##

Suitable solvents for the cyclisation include acetone and toluene, andsuitable bases include potassium carbonate, aqueous sodium hydroxide.

The use of aqueous sodium hydroxide solution, even at 80° C. does notcause any significant hydrolysis of the ester.

In the case of toluene/aqueous sodium hydroxide, a phase transfercatalyst (eg tetrabutylammonium bromide) may be added, resulting inaccelerating the reaction and allowing it to proceed at a lowertemperature.

The intermediate (B) may either be used as a crude oii or isolated as awhite crystalline solid and then cyclised in quantitative yield to givea solution of(A) in a suitable solvent (eg toluene) for coupling withthe amine.

Compounds of the formula (A) and (B) are novel and form an aspect of theinvention.

The following Example illustrates the invention. The followingDescription illustrates the preparation of an intermediate of formula(A).

EXAMPLE

i) Preparation ofN-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide[SB-207266]

Method A Toluene (85L) was azeotropically dried in an argon purgedreactor, cooled to 10° C. and a solution of trimethylaluminum in toluene(18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was addeda solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure,42.7 mole) in toluene (22 L) over 43 minutes. Methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9%pure, 41.3 mole) was added in one portion and the reaction heated toreflux at 112° C. for 4 hours 10 minutes after which time the reactionwas judged to be complete by HPLC analysis. 10% Sodium hydroxidesolution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) andwater (80 L), was added cautiously over 16 minutes at about 60 to 70° C.The resulting mixture was heated to 70 to 80° C. and the aqueous layerseparated. The toluene layer was washed with 10% sodium hydroxide (52.2L) followed twice by water (29 L each wash). The toluene layer wascooled and diluted with hexane fraction (133 L) to crystallise theproduct. After cooling to about 2° C. overnight the product wascollected by filtration, washed on the filter with hexane (21 L) anddried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8(12.26 kg, 94.5% pure, 75.9%).

Method B 1.6M Butyllithium in hexane (1.4 ml) was added to toluene (2ml) at -10°. A solution of 1-n-butyl-4-piperidinyimethylamine (0.38 g)in toluene (3 ml) was added and the mixture was stirred for 5 mins. Asolution of methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (0.23 g) in hottoluene (5ml) was added and the mixture was stirred at -10° for 5 mins.The mixture was diluted to 1000 ml with acetonitrile:water and relativeassay of the solution showed an SB-207266 content of 343mg (93% yield).

Method C A mixture of methyl 2-(3-chloropropoxy)-indole-3-carboxylate(100 g, 0.37 mol), aqueous sodium hydroxide solution (38 ml, 10.8M, 0.41mol), water (38 ml) and tetrabutylammonium bromide (6.0 g, 0.019 mol) intoluene (1000 ml) was stirred at 50-60° C. for about one hour. Water(120 ml) was added and the aqueous layer was removed. The organic layerwas washed with water (120 ml) and dried by azeotropic distillation oftoluene (250 m) giving a dry solution of methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate in toluene.This solution was cooled to ambient temperature and treated sequentiallywith a solution of 1-butyl-4-piperidinylmethylamine (66.8 g, 0.39 mol)in toluene (200 ml) followed by a solution of trimethylaluminium intoluene (196 ml, 2.0M, 0.39 mol). The mixture was heated to reflux andstirred for three hours. The reaction was quenched by cautious additionof aqueous sodium hydroxide solution (460 ml, 10% w/v) and then washedonce with aqueous sodium hydroxide solution (460 ml, 10% w/v) and twicewith water (275 ml each wash) while maintaining the temperature at about70° C. Toluene (200 ml) was added and the resulting solution was driedby azeotropic distillation of toluene (200 ml) at about 55° C. underreduced pressure. Hexane (1400 ml) was added and the resulting slurrycooled to about 0-5° C. for about one hour. The solid was isolated byfiltration and dried in vacuo to give the product,N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide,(114.7 g, 83%) as a white crystalline solid.

ii) Preparation ofN-[(1-butyl4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamidehydrochloride [SB-207266-A]

Method AN-[(1-Butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3.2-a]indole-10-carboxamide(SB-207266) (12.26 kg 94.5% pure. 31.35 moles) was dissolved in acetone(70.5 L) at 41° C. Anhydrous HCl in propan-2-ol (8.98 L, 3.86 molar,34.7 moles), made by dissolving HCl gas (3.1 kg) in propan-2-ol (20 L),was added over 8 minutes allowing the temperature to rise to 57° C. Themixture was cooled to 4° C. and stirred at 2 to 4° C. for 2 hours. Theprecipitate was filtered off washed with cold acetone (25 L) and driedat atmospheric pressure at 40 to 50° C. for 17 hours to give the crudeproduct as a white solid (12.94 kg; 96.1%).

The crude product (12.94 kg) was dissolved in hot ethanol (107 L) andfiltered through celite, washing the filter bed with further hot ethanol(18 L). The filtrate was heated to 75° C. and hot filtered hexane (68 L)was added. The mixture was cooled to 19° C. over about 4 hours and thento 4° C. and stirred overnight at 1° C. The white solid was filteredoff, washed with a 1:1 mixture of cold ethanol/hexane (27 L) and driedin vacuo at 50° C. for 23 hours to give SB-207266A (12.36 kg, 96.2% fromSB-207266). This was milled in an Apex Comminuting mill through a 0.125inch×0.125 inch square mesh at medium speed and with hammers forward.12.3 kg (95.8% from SB-207266) was isolated as a fine, homogeneous whitepowder.

Method BN-[(1-Butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide(SB-207266) (100 g, 0.27 mol) was dissolved in ethanol (870 ml) and theresulting solution filtered to remove particulates. Anhydrous HCl inethanol (83 ml, 3.6M, 0.30 mol) was added causing the product toprecipitate out of solution. The slurry was heated to redissolve thesolid and hexane (550 ml) was added. After cooling to room temperature,the mixture was cooled to 0-5° C. and stirred at that temperature forabout two hours. The solid was isolated by filtration and dried in vacuoat about 40° C. to give the product,N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide hydrochloride, (102.8 g) in 94% yield.

DESCRIPTION

Preparation of methyl-3,4dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate

Method A A solution of 3-chloropropanol (14.74 kg, 98.4% pure, 153.4mole) in dichloromethane (67 L) was cooled to -17° C. In a second vesseldichloromethane (68 L), methyl indole-3-carboxylate (13.5 kg, 99.8%pure, 76.9 mole) and 1,4-diazabicyclo[2.2.2]octane (4.75 kg, assumed100% pure, 42.3 mole) were cooled to 0° C. N-Clorosuccinimide (11.3 kg,99.5% pure, 84.2 mole) was added to the second vessel and stirred at 0°C. for 10 minutes. In the meantime methane sulphonic acid (0.59 L, 99.7%pure, 6.14 mole) was added to the first vessel. The solution in thesecond vessel was added to the first vessel over 49 minutes at -15 to 3°C. and the resulting mixture stirred for a further 31 minutes at -5 to0° C. 10% Sodium carbonate solution (147 L), made from sodium carbonate(42.2 kg, 398 mole) and process water (422 L), was added over 14 minutesand stirred. The organic layer was separated and washed twice with 10%sodium carbonate solution (147 L each wash). The organic layer was driedover anhydrous sodium sulphate, filtered and concentrated under reducedpressure below 30° C. The concentrate was dissolved in acetone (101 L)at about 18° C. and potassium carbonate (14.9 kg) added. The mixture wasstirred at 18 to 28° C. for 18 hours. Analysis of the reaction showed itto be complete. The inorganic salts were filtered off, the filtrateconcentrated under reduced pressure below 30° C. and dissolved indichloromethane (101 L). The dichloromethane solution was washed twicewith 5% sodium bicarbonate solution (85 L each wash), made from sodiumbicarbonate (8.3 kg) and water (167 L) and dried over anhydrous sodiumsulfate. After filtration the filtrate was concentrated under reducedpressure to a base temperature of about 95° C. and diluted with toluene(12 L). The toluene solution was cooled, causing the product tocrystallise and cooling continued to about 0° C. overnight. The productwas collected by filtration, washed on the filter with cold (0° C.)toluene (7 L) and dried in vacuo at 30° C. for 21 hours to give thetitle compound (9.654 kg, 98.9% pure, 53.7%).

Method B A solution of 3-chloropropanol (142.47 g, 1.51 mole) indichloromethane (1200 ml) was cooled to -20° C. In a second vesseldichloromethane (1300 ml), methyl indole-3-carboxylate (240.0 g, 1.37mole) and 1,4-diazabicyclo[2.2.2]octane (84.52 g 0.75 mole) were cooledto 0° C. N-Chlorosuccinimide (201.22 g 1.51 mole) was added to thesecond vessel and stirred at 0° C. for 10 minutes. In the meantimemethane sulphonic acid (10.56 ml) was added to the first vessel. Thesolution in the second vessel was added to the first vessel keeping thetemperature below about 0° C., and the resulting mixture stirred for afurther 2.5 hours at -5 to 0° C. 10% Sodium carbonate solution (2500 ml)was added and stirred. The organic layer was separated and washed twicewith 10% sodium carbonate solution (2500 ml each wash). The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The concentrate was triturated with ethylacetate (120 ml) and the mixture stirred at 0° C. for about 1 hour. Theresulting solid was filtered, washed a small quantity of ethyl acetateand dried under vacuum to give methyl2-(3-chloropropoxy)-indole-3-carboxylate (202.5 g) as a whitecrystalline solid in 55% yield.

A mixture of methyl 2-(3-chloropropoxy)-indole-3-carboxylate (81.5 g,0.304 mole), aqueous sodium hydroxide solution (3 ml, 10.8M, 0.335mole), water (31 ml) and tetrabutylammonium bromide (4.9 g, 0.015 mole)in toluene (815 ml ) was stirred at 50-60° C. for about 45 minutes. Theaqueous layer was removed and the organic layer washed twice with water(100 ml each wash). The resulting toluene solution was dried byazeotropic distillation of solvent (265 ml ) under reduced pressure (60°C., 160 mbar) giving a dried solution of the title compound in toluene.

Method C A solution of 3-chloropropanol (142.47 g, 1.51 mol) indichloromethane (1200ml) was cooled to -20° C. In a second vesseldichloromethane (1300 ml), methyl indole-3-carboxylate (240.0 g, 1.37mol) and 1,4-diazabicyclo[2.2.2]octane (84.52 g 0.75 mol) were cooled to0° C. N-Chlorosuccinimide (201.22 g 1.51 mole) was added to the secondvessel and stirred at 0° C. for 10 minutes. In the meantime methanesulfonic acid (10.56 ml) was added to the first vessel. The solution inthe second vessel was added to the first vessel keeping the temperaturebelow about 0° C., and the resulting mixture stirred for a further 2.5hours at -5 to 0° C. 10% Sodium carbonate solution (1250 ml) was addedand the mixture stirred for about 30 minutes. The organic layer wasseparated and washed once more with 10% sodium carbonate solution (1250ml) and once with water (1250 ml). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The concentrate was triturated with toluene (400 ml) and themixture stirred at 0° C. for about 1 hour. The resulting solid wasfiltered, washed with toluene and dried in vacuo to give methyl2-(3-chloropropoxy)-indole-3-carboxylate (245.5 g) as a whitecrystalline solid in 67% yield.

What is claimed is:
 1. A process for the preparation ofN-[(1-n-butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideor a pharmaceutically acceptable salt thereof, which process comprisesthe reaction of of N-(1-^(n) butyl-4-piperidyl)methylamine with acompound of formula (A): ##STR7## wherein R is alkyl.
 2. A processaccording to claim 1 wherein R is methyl or ethyl.
 3. A processaccording to claim 1 wherein the reaction is catalysed by a aluminum orlithium based catalyst.
 4. A process according to claim 3 wherein thecatalyst is trimethylaluminum.
 5. A compound of formula (A): ##STR8##wherein R is alkyl.
 6. Methyl-3,4dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
 7. A compound offormula (B): ##STR9## Processes for the preparation ofN-[(1-nbutyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-A]indole-10-carboxamideand its salts are provided.